This section provides background information related to the present disclosure which is not necessarily prior art.
Regadenoson, which chemical name is (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide, has a structural formula as follows:
U.S. Pat. No. 6,403,567B1 firstly disclosed regadenoson as well as a preparation method and use thereof. Regadenoson is an adenosine A2A receptor agonist with high selectivity, used as a stress agent for radionuclide myocardial perfusion imaging, which has been clinically applied as a cardiac vasodilator for cardiac imaging in USA.
Polymorphism in pharmaceuticals is a common phenomenon in drug research and development, and is an important factor which influences drug quality. Polymorphism refers to a phenomenon that the same compound can form two or more molecularly spatial arrangements by controlling different generation conditions, thus to generate different crystalline solids. Different crystal forms of the same compound have the same chemical composition, but have different crystal microstructures, thus leads to difference in their morphological appearance, physicochemical property and bioactivity. Different crystal forms of a drug often have different solubility, storage stability, hygroscopicity, density and bioavailability. The crystal form of a drug directly affects the quality and absorption behavior in human body of a pharmaceutical preparation of the drug, and finally affects the benefit ratio between the therapeutic effect and side effect of the preparation in human body. Therefore, researches on the polymorphism of a drug and preparation methods for different crystal forms thereof are of great significance.
Currently, it is known that regadenoson exists in various crystal forms. U.S. Pat. No. 7,732,595 disclosed many crystal forms of regadenoson, including crystal forms A, B, C, and an amorphous form.
Crystal form A (as shown in FIG. 1) was produced by crystallization from a protic solvent or a polar solvent, such as ethanol or a mixed solvent of ethanol and water, or a mixed solution of N,N-dimethylsulfoxide and water. Crystal form A is a monohydrate, and is the most stable among the various crystal forms of regadenoson, which is stable under heating under relative humidity stress conditions up to its melting point. However, due to the very poor solubility of regadenoson, it is mostly insoluble in common solvents, is slightly soluble in water, and is difficult to be dissolved by a mixed solvent of protic solvents alcohols and water. As such, crystal form A is not suitable for scale production and preparation. Moreover, when crystal form A is prepared by using a mixed solution of DMSO and water, it is very difficult to remove DMSO thoroughly due to its extremely high melting point up to 189° C., thus failing to obtain crystal form A at a high purity.
Crystal form B (as shown in FIG. 2) was a crystal form obtained by dissolving regadenoson in a solvent trifluoroethanol at ambient temperatures followed by concentrating under reduced pressure. Such a crystal form was distinctly different from other crystal forms, which X-ray analysis gave disordered broad peaks. The crystal form contains varying amounts of crystal water, and it is very difficult to reproduce the preparation process thereof.
A new crystal form solid obtained by slurrying regadenoson in acetonitrile for a long time at 60° C. followed by filtration, is crystal form C (as shown in FIG. 3). Such a crystal form also contains uncertain content of crystal water, and is unstable after losing crystal water under a high temperature.
The amorphous form of regadenoson was formed by heating crystal form A up to 200° C., which, however, is unstable in atmospheric moisture, forming various crystalline hydrates thereof.
International Patent WO2012149196 reports crystal form D of regadenoson (as shown in FIG. 4) and a preparation method thereof. Regadenoson was dissolved in a mixed solution of methanol and water via reversed phase chromatography, and concentrated to a paste; the paste was heated in an oil-bath to 150° C. under a reduced pressure of 20 mmHg for 6 hours to afford crystal form D as a white solid, which contained 0.8-1.7% of crystal water. However, the method as described in this patent is a too complicated and rigorous process, is difficult to be reproduced and scaled up, and needs to be heated to a high temperature up to 150° C. which easily causes the decomposition of the compound.